Field of the Invention
This invention is in the field of bone hemostasis and involves a method and materials to stop bleeding from bony surfaces via application of copolymers of oxyethylene and oxypropylene during operative procedures or trauma.
Background
During many operative procedures and/or trauma, bones bleed. When such bone bleeding is undesirable and needs to be controlled, cessation of the bleeding, or “hemostasis,” has been achieved by several methods in the past. The following methods are presently used to achieve bone hemostasis in surgery requiring fusion of bones:                1. The bones can be permitted to bleed and external drainage can be made for postoperative hematomas;        2. Gel foam or cellulose can be applied locally to the bones;        3. Direct electrocautery can be applied to bleeding bone surfaces;        4. Use of a mechanical barrier such as “bonewax” can be applied to the bones.        
Bonewaxes used in surgery today are generally prepared from refined beeswax which has been admixed with other nonabsorbable and water insoluble hydrocarbons and vegetable oils. Certain disadvantages are inherent in these bonewax compositions, such as poor adhesion qualities and brittleness of the wax at room temperatures. In addition, paraffin-based commercial bonenwax is not absorbed by the body and thus remains at the site of the application for long periods of time. As a result, the wax acts as a foreign material tending to make it difficult for the body to fight infection and causing inflammatory reactions that may be introduced into the surrounding tissue. Moreover, the wax interferes with bone regrowth. In addition, bonewax has shown a possible association with increased chromosomal aberrations and teratogenesis in mice. Finally, traditional bonewax has often resulted in the formation of granulomas (a nodular aggregation of inflammatory cells associated with chronic inflammation, which deters proper healing of separated bones and surrounding tissue).
The following have been reported as substitutes for bonewax: gel foam (gelatin) paste; microcrystalline collagen, fibrin-collagen paste, and bioerodible polyorthoester (Alzamer®).
The desirable characteristics in a bone hemostasis agent are: (1) no detrimental effects on bony fusion, (2) non-inflammatory; (3) no increased infection rate; (4) non-toxic; (5) inexpensive; (6) non-teratogenic; (7) effective at achieving bone hemostasis quickly; (8) easily resorbed by the body; (9) not metabolized by the body, which prevents possible toxicity from the compound; (10) water soluble; (11) easily prepared; (12) easy to maintain quality control; (13) maintains chemical stability for long periods of time at room temperature; (14) similar consistency to currently used beeswax. None of the above-listed agents, known agents, or traditional bonewaxes have proven satisfactory in satisfying all these characteristics for a bone hemostasis agent.
The current invention involves the use of copolymers of oxyethylene and oxypropylene. Such copolymers include poloxamers, meroxapols (also known as reverse poloxamers), poloxamines, and PLURADOT® or PLURACOL® (the proprietary name given by the manufacturer BASF; there is no non-proprietary name for PLURADOT®). The principal supplier of these copolymers is BASF, and BASF has given these copolymers the following proprietary names: poloxamers are known as PLURONIC® surfactants; meroxapols are known as PLURONIC® R surfactants; poloxamines are known as TETRONIC® surfactants; and PLURACOL® surfactants. As used throughout this application the terms “copolymers of oxyethylene and oxypropylene” are inclusive of all four of the above listed BASF copolymers. As used throughout this application, the term “PLURONIC®s” is also inclusive of all four of the above-listed BASF copolymers, except as the context otherwise requires, such as in the case of discussing specific examples of specific poloxamers.
PLURONIC® copolymers are organic polymers of varying chain lengths and oxyethylene and oxypropylene ratios. They were developed in the 1950's by BASF and have a number of medical uses. Such PLURONIC®s are currently available at low cost. For a general discussion of PLURONIC®s, see Schmolka. I. J., Journal of American Oil and Chemical Society. A Review of Block Polymer Surfactants, 54:110 (1977) (which is incorporated by reference as if fully set forth herein) A general discussion is also included below in the Examples section.
PLURONIC® copolymers are currently used in variety of medical settings, including suture coating, suppositories, intravenous injection to improve blood rheology, and as an additive in artificial blood substitutes. PLURONIC®s have also been utilized to promote osteogenesis when mixed with demineralized bone powder. Although PLURONIC®s have been used as merely additives in some bone hemostasis agents, no bone hemostasis agent has utilized PLURONIC®s as the base material for the agent, as does this invention.
Bone morphogenetic proteins (BMPs) can promote bone regeneration. Schmitt, J. M., Hwang, K., Winn, S. R., Hollinger, J. O., “Bone Morphogenetic Proteins: An Update on Basic Biology and Clinical Relevance”, J. Orthop. Res., 1999, 17(2), 269-278 (which is incorporated by reference as if fully set forth herein). However, BMPs applied to a site of bone injury will be rapidly resorbed, and therefore will have minimal efficacy, unless they are administered via an appropriate system to maintain sustained delivery of the protein during the course of bone healing. Solheim, E., “Growth Factors in Bone”, Int. Orthop., 1998, 22(6), 410-416 (which is incorporated by reference as if fully set forth herein). Incorporation of BMPs with bonewax is a very desirable solution as it (a) enhances the therapeutic value of the bonewax; and (b) eliminates the need for a separate sustained delivery system for the BMPs. However, the required property of any material intended as a BMP delivery system is that it should be water soluble or water permeable. Current beeswax based bonewaxes are insoluble and impermeable to water and thus would not fulfill this requirement. However, PLURONIC® copolymers are water soluble and hence would serve as an ideal system to sustain BMP delivery.